title: Mapping of the disease locus and identification of ADAMTS10 as a candidate gene in a canine model of primary open angle glaucoma.
abstract: Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide, with elevated intraocular pressure as an important risk factor. Increased resistance to outflow of aqueous humor through the trabecular meshwork causes elevated intraocular pressure, but the specific mechanisms are unknown. In this study, we used genome-wide SNP arrays to map the disease gene in a colony of Beagle dogs with inherited POAG to within a single 4 Mb locus on canine chromosome 20. The Beagle POAG locus is syntenic to a previously mapped human quantitative trait locus for intraocular pressure on human chromosome 19. Sequence capture and next-generation sequencing of the entire canine POAG locus revealed a total of 2,692 SNPs segregating with disease. Of the disease-segregating SNPs, 54 were within exons, 8 of which result in amino acid substitutions. The strongest candidate variant causes a glycine to arginine substitution in a highly conserved region of the metalloproteinase ADAMTS10. Western blotting revealed ADAMTS10 protein is preferentially expressed in the trabecular meshwork, supporting an effect of the variant specific to aqueous humor outflow. The Gly661Arg variant in ADAMTS10 found in the POAG Beagles suggests that altered processing of extracellular matrix and/or defects in microfibril structure or function may be involved in raising intraocular pressure, offering specific biochemical targets for future research and treatment strategies.
authors.affiliation: Vanderbilt Eye Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America. rachel.kuchtey@vanderbilt.edu
authors.forename: John
authors.initials: J
authors.lastname: Kuchtey
authors.forename: Lana M
authors.initials: LM
authors.lastname: Olson
authors.forename: Tommy
authors.initials: T
authors.lastname: Rinkoski
authors.forename: Edward O
authors.initials: EO
authors.lastname: Mackay
authors.forename: T M
authors.initials: TM
authors.lastname: Iverson
authors.forename: Kirk N
authors.initials: KN
authors.lastname: Gelatt
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Rachel W
authors.initials: RW
authors.lastname: Kuchtey
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D056426:Genetic Loci / Q000235:genetics*; D016678:Genome / Q000235:genetics; D005902:Glaucoma, Open-Angle / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D014129:Trabecular Meshwork / Q000378:metabolism / Q000473:pathology
chemical_list: D051722:ADAM Proteins